Dry eye disease (DED) is a complex multifactorial disease of the ocular surface which is observed clinically with signs and reported patient symptoms. The Tear Film & Ocular Surface Society Dry Eye Workshop II (TFOS DEWS II) published in 2017 provided clinicians with a diagnostic algorithm as well as a stepwise approach to management of DED.1,2 Early interventions for DED include education, ocular lubricants, omega-3 supplementation and lid therapy, whereas additive treatments include overnight ointments, anti-inflammatories, in-office meibomian gland warming devices, tear conservation, dry eye therapeutics, and more.2 To date, the majority of DED therapeutics have been administered through an ophthalmic (i.e., loteprednol, cyclosporine, lifitegrast) or oral (i.e., doxycycline) route. These have been largely successful, but also have limitations and inconveniences such as the dosage frequency, ocular irritation due to preservatives and other ophthalmic ingredients, and potential gastric irritation of oral substances.

Novel medication for dry eye disease

The first nasal spray medication approved by the US Food & Drug Administration (FDA) for DED explores a different route of administration and mechanism of action. Varenicline (commercially available as Tyrvaya®), is a nicotinic acetylcholine receptor agonist that is available as a nasal spray. Its mode of action is believed to stimulate the trigeminal nerve endings in the nasal cavity, which in turn activate the nasolacrimal reflex to increase tear production. As a new medication, this article performed a systemic review and meta-analysis of randomized controlled trials (RCTs) to assess the efficacy and safety of different doses of varenicline nasal spray in the management of DED.

The review included strict search parameters which involved RCTs comparing varenicline to placebo and had a Schirmer test score at baseline and after 28 days as a primary endpoint. Three doses are available for varenicline: 0.12 mg/ml (low), 0.6 mg/ml (mid) and 1.2 mg/ml (high). However, since only a single RCT was available for the low dose, the article only reviewed RCTs using mid and high doses. In addition, serious adverse events (SAEs) and adverse events (AEs) were investigated for safety of the drug.

A search for articles in Medline, Embase and Cochrane Central Register of Controlled Trials (CENTRAL) was performed by two reviewers and screened for eligibility criteria. Three RCTs (n=3) were retained for analysis representing 1063 participants (mean age 51.4 to 67.4 years, 76.5% female, 22.7% Latino or Hispanic).

In terms of efficacy, the meta-analysis revealed that both the mid and high doses of varenicline showed significant improvements in the Schirmer test score after 28 days versus placebo (mid-dose standardized mean difference [SMD]=5.67, 95% CI 1.58-9.76, p=0.007; high-dose SMD=5.73, 95% CI 2.32-9.14, p=0.001).

Neither dose of varenicline had an increased risk of SAEs over the placebo, nor were there any statistically significant increases in conjunctival hyperemia (p=0.96) or reductions in visual acuity (p=0.94). Nasal cavity AEs included increased sneezing, but the authors reported in the text that this did not reach statistical significance in either dose group (mid-dose p=0.08; high-dose p=0.06). However, Figure 8 shows contradictory results to this statement, with a high-dose overall effect of p=0.04, which would be statistically significant. At the time of publication, attempts to contact the first author to clarify this discrepancy have thus far gone unanswered. Other noted adverse events were coughing and throat irritation, which were greater in the nasal spray groups (all mid- and high-dose p<0.00001) versus placebo, but there was no dose-related difference.

The authors provided forest plots to visualize the effect of varenicline on the Schirmer test score (mid-dose p=0.007; high-dose p=0.001), SAEs (mid-dose p=0.38; high-dose p=0.47), ocular AEs (mid-dose p≥0.40; high-dose p≥0.44), and nasal cavity-related AEs (coughing and throat irritation all mid- and high-dose p<0.00001), to visualize the combined results of the meta-analysis.

One of the measures reported in a meta-analysis is heterogeneity, expressed as a I2 value. Studies differ in their methodology, randomization, selection of population, and other biases, potentially resulting in a heterogenous sample of studies. In this review, the authors reported a considerable heterogeneity (I2=99%) for the Schirmer test score after 28 days compared to baseline, even though the individual and pooled data favored a positive outcome when using varenicline. The authors reported that some of the heterogeneity may be because one of the RCTs conducted by Quiroz-Mercado et al.3 was a single site study which consisted of only Hispanic or Latino participants. Although this population selection is important to supplement our collective DED knowledge in this ethnic group, other clinical trials on DED are multi-centered and represent a variety of ethnic backgrounds. Sneezing also revealed a moderate heterogeneity for both the mid (I2=68%) and high (I2=64%) doses of varenicline. The patient selection, along with limited number of RCTs on this novel intervention for DED, may have contributed to the heterogeneity. Conversely, the heterogeneity for SAEs, ocular AEs (hyperemia and reduced visual acuity) and nasal-cavity-related AEs (coughing and throat irritation) were all very low (I2=0%) for both doses of varenicline.

Implications for clinical practice of a novel DED intervention

DED management typically requires three to four different interventions,4 as no single treatment has proven to be effective. In most instances, entry-level management includes ocular lubricants, which come with challenges of insertion, dosage, preservatives, cost and have the potential to transiently disturb vision. Varenicline is a novel medication using a non-ophthalmic route of administration dosed twice a day, 12 hours apart. This dosing regimen is advantageous to patients who can use it before and after work/school and do not have the burden of needing to carry it with them during the day. Furthermore, a nasal spray may have advantages over artificial tears for those that are anxious or have difficulty (i.e., arthritis) with instilling eye drops.

In summary

This meta-analysis demonstrated that varenicline nasal spray is an effective treatment for DED, with cough and throat irritation as primary adverse events. More studies are needed to assess the longer term (>28 days) effects of varenicline, with larger populations, different dosages, and comparisons with existing DED medication. Varenicline nasal spray provides clinicians with a novel option in their armamentarium for the management of DED patients.


  1. Wolffsohn JS, Arita R, Chalmers R, et al. TFOS DEWS II diagnostic methodology report. Ocul Surf. 2017;15:539-74.
  2. Jones L, Downie LE, Korb D, et al. TFOS DEWS II management and therapy report. Ocul Surf. 2017;15:575-628.
  3. Quiroz-Mercado H, Hernandez-Quintela E, Hsun Chiu K, et al. A phase II randomized trial to evaluate the long-term (12-week) efficacy and safety of OC-01 (varenicline solution) nasal spray for dry eye disease: The MYSTIC studyOcul Surf. 2022;24: 215-21.
  4. Bitton E, Elder M, Srinivasan S, et al. Dry eye disease in university-based clinics in Canada: A retrospective chart review. Optom Vis Sci. 2020;97:944-53.